The goal of this proposal is to elucidate the mechanisms involved in the progression of hypertension-induced end organ damage when a compensatory vasoactive substance has been removed using a gene targeting approach. Calcitonin gene related peptide. CGRP, is a 37 amino acid neuropeptide that has been shown to be the most potent vasodilator discovered to date. Receptors for CGRP have been identified in resistance vessels and administration of exogenous CGRP has been shown to decrease blood pressure in a dose-dependent manner and dilate multiple vascular beds. Using a CGRP/calcitonin knockout (KO) mouse model, preliminary data has demonstrated an increase in basal mean arterial blood pressure and a decrease in basal coronary blood flow. Hypertensive KO mice also display markedly enhanced heart and kidney damage. Recently, the development of oxidative stress and reactive oxygen species (ROS) has been implicated in hypertension-induced end organ damage, a common consequence of chronic elevated blood pressure. Thus, the purpose of this proposal is to identify the specific mechanisms involved in the interaction between the compensatory actions of CGRP and the production of ROS in hypertension-induced end organ damage.